Quality of life among women with interstitial cystitis.
Clinical case series suggest that the impact of interstitial cystitis on quality of life is severe and debilitating, however, little epidemiologic information is available. We examined the impact of interstitial cystitis on quality of life in a population based cohort of United States women. We collected multidimensional measures of quality of life from 159,419 participants in the Nurses' Health Study I and II using a validated instrument, the Medical Outcome Study Short-Form 36 Health Survey Instrument. This instrument measures physical function, role limitations due to physical and emotional problems, bodily pain, vitality, social function and mental health. Quality of life measures were collected on 99 women with prevalent self reported interstitial cystitis confirmed by medical record review. After adjusting for age and co-morbid conditions, women with interstitial cystitis had significantly lower quality of life scores in 4 of the 7 quality of life dimensions, including role/physical (beta -13.1, p <0.001), bodily pain (beta -9.8, p <0.001), vitality (beta -7.7, p <0.001) and social function (beta -7.2, p <0.001) compared to women without interstitial cystitis. Women with interstitial cystitis experienced less decrement in physical function compared to women with rheumatoid arthritis but more compared to women with hypertension. In addition, they experienced greater differences in vitality and mental health than women with rheumatoid arthritis or hypertension. The quality of life among women with interstitial cystitis was especially limited in the psychosocial dimensions, such as vitality and mental health. Future research on interstitial cystitis should incorporate multidimensional measures of quality of life, especially with respect to response to the various treatments.


Imaging Distal Aqueous Outflow Pathways in a Spontaneous Model of Congenital Glaucoma.
To validate the use of aqueous angiography (AA) in characterizing distal aqueous outflow pathways in normal and glaucomatous cats. Ex vivo AA and optical coherence tomography (OCT) were performed in nine adult cat eyes (5 feline congenital glaucoma [FCG] and 4 normal), following intracameral infusion of 2.5% fluorescein and/or 0.4% indocyanine green (ICG) at physiologic intraocular pressure (IOP). Scleral OCT line scans were acquired in areas of high- and low-angiographic signal. Tissues dissected in regions of high- and low-AA signal, were sectioned and hematoxylin and eosin (H&E)-stained or immunolabeled (IF) for vascular endothelial and perivascular cell markers. Outflow vessel numbers and locations were compared between groups by Student's t-test. AA yielded circumferential, high-quality images of distal aqueous outflow pathways in normal and FCG eyes. No AA signal or scleral lumens were appreciated in one buphthalmic FCG eye, though collapsed vascular profiles were identified on IF. The remaining eight of nine eyes all showed segmental AA signal, distinguished by differences in time of signal onset. AA signal always corresponded with lumens seen on OCT. Numbers of intrascleral vessels were not significantly different between groups, but scleral vessels were significantly more posteriorly located relative to the limbus in FCG. A capacity for distal aqueous humor outflow was confirmed by AA in FCG eyes ex vivo but with significant posterior displacement of intrascleral vessels relative to the limbus in FCG compared with normal eyes. This report provides histopathologic correlates of advanced diagnostic imaging findings in a spontaneous model of congenital glaucoma.


An Arabidopsis ATPase gene involved in nematode-induced syncytium development and abiotic stress responses.
The beet cyst nematode Heterodera schachtii induces syncytia in the roots of Arabidopsis thaliana, which are its only nutrient source. One gene, At1g64110, that is strongly up-regulated in syncytia as shown by RT-PCR, quantitative RT-PCR, in situ RT-PCR and promoter::GUS lines, encodes an AAA+-type ATPase. Expression of two related genes in syncytia, At4g28000 and At5g52882, was not detected or not different from control root segments. Using amiRNA lines and T-DNA mutants, we show that At1g64110 is important for syncytium and nematode development. At1g64110 was also inducible by wounding, jasmonic acid, salicylic acid, heat and cold, as well as drought, sodium chloride, abscisic acid and mannitol, indicating involvement of this gene in abiotic stress responses. We confirmed this using two T-DNA mutants that were more sensitive to abscisic acid and sodium chloride during seed germination and root growth. These mutants also developed significantly smaller roots in response to abscisic acid and sodium chloride. An in silico analysis showed that ATPase At1g64110 (and also At4g28000 and At5g52882) belong to the 'meiotic clade' of AAA proteins that includes proteins such as Vps4, katanin, spastin and MSP1.


Phosphorylation and dephosphorylation among Dif chemosensory proteins essential for exopolysaccharide regulation in Myxococcus xanthus.
Myxococcus xanthus social gliding motility, which is powered by type IV pili, requires the presence of exopolysaccharides (EPS) on the cell surface. The Dif chemosensory system is essential for the regulation of EPS production. It was demonstrated previously that DifA (methyl-accepting chemotaxis protein [MCP]-like), DifC (CheW-like), and DifE (CheA-like) stimulate whereas DifD (CheY-like) and DifG (CheC-like) inhibit EPS production. DifD was found not to function downstream of DifE in EPS regulation, as a difD difE double mutant phenocopied the difE single mutant. It has been proposed that DifA, DifC, and DifE form a ternary signaling complex that positively regulates EPS production through the kinase activity of DifE. DifD was proposed as a phosphate sink of phosphorylated DifE (DifE approximately P), while DifG would augment the function of DifD as a phosphatase of phosphorylated DifD (DifD approximately P). Here we report in vitro phosphorylation studies with all the Dif chemosensory proteins that were expressed and purified from Escherichia coli. DifE was demonstrated to be an autokinase. Consistent with the formation of a DifA-DifC-DifE complex, DifA and DifC together, but not individually, were found to influence DifE autophosphorylation. DifD, which did not inhibit DifE autophosphorylation directly, was found to accept phosphate from autophosphorylated DifE. While DifD approximately P has an unusually long half-life for dephosphorylation in vitro, DifG efficiently dephosphorylated DifD approximately P as a phosphatase. These results support a model where DifE complexes with DifA and DifC to regulate EPS production through phosphorylation of a downstream target, while DifD and DifG function synergistically to divert phosphates away from DifE approximately P.


Protective Effect of HLA-E∗0101∕∗0103 Genotype in Survival of Patients After Allogeneic Hematopoietic Stem Cell Transplant.
HLA-E is located on the nonclassical major histocompatibility complex class I and acts as the ligand for natural killer cells. Consequently, it has a main role in the regulation of innate immune responses by involving cell identification by natural killer cells. Differences in expression levels among HLA-E alleles have been suggested to affect transplant outcomes. In this study, we evaluated the effects of different HLA-E genotypes on allogeneic hematopoietic stem cell transplant in southern Iran. We investigated 200 patients (donors and recipients) who underwent allogeneic hematopoietic stem-cell transplant and 100 normal participants (control group) in a case-control study. Detection of HLA-E polymorphisms was performed using a sequence-specific primer polymerase chain reaction method. Statistical analyses indicated that genotypes in the transplant group were not distributed in accordance with Hardy-Weinberg equilibrium (χ²=76.56; P < .001), whereas genotypes in the control group were distributed in accordance with Hardy-Weinberg equilibrium (χ²=0.39; P = .53). No significant differences were observed in cumulative incidence of acute (P = .76; hazard ratio = 0.80; 95% confidence interval, 0.19-3.31) and chronic (P = .75, hazard ratio = 0.048; 95% confidence interval, 0.00) graft-versus-host disease in recipients harboring HLA-E∗0103 allele compared with those homozygous for the HLA-E∗0101 allele. The HLA-E∗0103 allele showed a trend toward lower cumulative incidence of relapse compared with the homozygous HLA-E∗0101 genotype (8% vs 21.5%; P = .37; hazard ratio = 2.50; 95% confidence interval, 0.32-19.20). Genotypes of the HLA-E molecule did not correlate with acute and chronic graft-versus-host disease in hematopoietic stem cell transplant recipients except for the HLA-E∗0101∗∕∗0103 genotype, which was protective in survival of our study patients.


ApoE Mimic Peptide COG1410 Reduces Aβ Deposition and Improves Cognitive Function by Inducing the Transformation of A1/A2 Reactive Astrocytes and Increasing the BDNF Concentration in Brain of APP/PS1 Double Transgenic Mice.
The main clinical manifestation of Alzheimer's disease is progressive cognitive decline, and its pathological features are β-amyloid (Aβ) deposition, neurofibrillary tangles, synaptic dysfunction and neuron death. Neuroinflammation is an important reason for the occurrence and development of AD, which is mainly manifested by the accumulation of activated microglia and reactive astrocytes. Apolipoprotein E (ApoE) is one of the most important apolipoprotein in the brain, which is related to metabolism, aggregation and toxicity of Aβ. However, the underlying mechanism needs to be further explored. In this study, we studied the effect of ApoE mimetic peptide COG1410 on spatial learning and memory functions, deposition of Aβ in the dentate gyrus (DG) of APP/PS1 transgenic mice, and the different effects of A1 and A2 subtypes of reactive astrocytes. Administration of COG1410 effectively improved performance in spatial learning and memory of APP/PS1 mice, reduced Aβ deposition and significantly reverted the ratio of A1/A2 reactive astrocytes, which could be associated with BDNF/TrkB signaling pathway. On the whole, the present findings suggest new possibility of using apolipoprotein E mimetic peptide to treat AD with potential effectiveness.


Recent Progress in Metal-Organic Framework-Derived Nanostructures in the Removal of Volatile Organic Compounds.
Air is the most crucial and life-supporting input from nature to the living beings of the planet. The composition and quality of air significantly affects human health, either directly or indirectly. The presence of some industrially released gases, small particles of anthropogenic origin, and the deviation from the normal composition of air from the natural condition causes air pollution. Volatile organic compounds (VOCs) are common contaminants found as indoor as well as outdoor pollutants. Such pollutants represent acute or chronic health hazards to the human physiological system. In the environment, such polluted gases may cause chemical or photochemical smog, leading to detrimental effects such as acid rain, global warming, and environmental pollution through different routes. Ultimately, this will propagate into the food web and affect the ecosystem. In this context, the efficient removal of volatile organic compounds (VOCs) from the environment remains a major threat globally, yet satisfactory strategies and auxiliary materials are far from being in place. Metal-organic frameworks (MOFs) are known as an advanced class of porous coordination polymers, a smart material constructed from the covalently bonded and highly ordered arrangements of metal nodes and polyfunctional organic linkers with an organic-inorganic hybrid nature, high porosities and surface areas, abundant metal/organic species, large pore volumes, and elegant tunability of structures and compositions, making them ideal candidates for the removal of unwanted VOCs from air. This review summarizes the fundamentals of MOFs and VOCs with recent research progress on MOF-derived nanostructures/porous materials and their composites for the efficient removal of VOCs in the air, the remaining challenges, and some prospective for future efforts.


Creation of an intramedullary cavity by hemorrhagic necrosis removal 24 h after spinal cord contusion in rats for eventual intralesional implantation of restorative materials.
Intramedullary hemorrhagic necrosis occurs early after spinal cord injury at the site of injury and adjacent segments. It is considered harmful because of its potential to aggravate secondary injury, and to interfere with axonal regeneration; it might also lead to an unfavorable environment for intralesional implants. Removal of hemorrhagic necrosis has been attempted before with variable results. The invasive nature of these procedures carries the risk of exacerbating damage to the injured cord. The overall objective for this study was to test several strategies for non-damaging removal of hemorrhagic necrosis and characterize the resulting cavity looking for a space for future intralesional therapeutic implants in rats with acute cord injury. Rats were subjected to graded cord contusion, and hemorrhagic necrosis was removed after 24h. Three grades of myelotomy (extensive, medium sized, and small) were tested. Using the small surgical approach to debridement, early and late effects of the intervention were determined by histology and by analytical and behavioral analysis. Appearance and capacity of the resulting cavity were characterized. Satisfactory removal of hemorrhagic necrosis was achieved with all three surgical approaches to debridement. However, bleeding in spared cord tissue was excessive after medium sized and extensive myelotomies but similar to control injured rats after small cord surgery. Small surgical approach to debridement produced no swelling nor acute inflammation changes, nor did it affect long-term spontaneous locomotor recovery, but resulted in modest improvement of myelination in rats subjected to both moderate and severe injuries. Cavity created after intervention was filled with 10 to 15 μL of hydrogel. In conclusion, by small surgical approach to debridement, removal of hemorrhagic necrosis was achieved after acute cord contusion thereby creating intramedullary spaces without further damaging the injured spinal cord. Resulting cavities appear suitable for future intralesional placement of pro-reparative cells or other regenerative biomaterials in a clinically relevant model of spinal cord injury.


The natural history of untreated sporadic vestibular schwannomas: a comprehensive review of hearing outcomes.
Observation is an important consideration when discussing management options for patients with vestibular schwannoma (VS). Most data regarding clinical outcomes after conservative management come from modestsized series performed at individual centers. The authors performed an analysis of the published literature on the natural history of VSs with respect to hearing outcome. Their objective was to provide a comprehensive and unbiased description of outcomes in patients whose disease was managed conservatively. The authors identified a total of 34 published studies containing hearing outcome data in patients with VSs < 25 mm in largest diameter who underwent observation management. The effects of initial tumor size and tumor growth rate on hearing function at latest follow-up were analyzed. Data from individual and aggregated cases were extracted from each study. Patients with poorer hearing (American Association of Otolaryngology-Head and Neck Surgery Classes C or D, or Gardner-Robertson Classes III, IV, or V) at the time of presentation were excluded. A total of 982 patients met the inclusion criteria for this analysis, with a mean initial tumor size of 11.3 +/- 0.68 mm. The mean growth rate was 2.9 +/- 1.2 mm/year. The length of follow-up for these studies ranged from 26 to 52 months. Patients with preserved hearing at latest follow-up had a statistically larger initial tumor size than those whose hearing declined during the observation period (11.5 +/- 2.3 mm vs 9.3 +/- 2.7 mm, p < 0.0001), but the 2-mm difference of means was at the limit of imaging resolution and observer reliability. In contrast, patients with lower rates of tumor growth (<or= 2.5 mm/year) had markedly higher rates of hearing preservation (75 vs 32%, p < 0.0001) compared with patients with higher tumor growth rates. Interestingly, the authors' analysis found no difference in the rate of reported intervention for patients in either group (16 vs 18%, p = not significant). These data suggest that a growth rate of > 2.5 mm/year is a better predictor of hearing loss than the initial tumor size for patients undergoing observation management of VSs < 25 mm in largest diameter.


Evaluation of oxidant-antioxidant status in tissue samples in oral cancer: A case control study.
Imbalances between the oxidant-antioxidant status have been implicated in the pathogenesis of several diseases, including cancer. The aim of this study was to evaluate the extent of lipid peroxidation and antioxidants in the tissue samples of oral squamous cell carcinoma (OSCC) patients of different clinical stages in comparison with the healthy controls. A case-control study was designed with 20 new histopathologically proven oral carcinoma patients and an equal number of age, sex, and tobacco chewing habit matched healthy subjects. Their tissue samples were subjected to evaluation of lipid peroxidation product and antioxidant enzymes, namely, superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), and glutathione peroxidase (GPx) using spectrophotometric methods. The data are expressed as mean ± standard deviation. The statistical comparisons between the study groups were performed by independent Student's unpaired t-test and one-way analysis of variance. Post-hoc analysis was performed for within study group comparisons. Karl Pearson correlation was performed for the biochemical parameters within the group and between the groups. For statistically significant correlations, simple linear regression was performed using SPSS (α=0.05). Significant reduction in lipid peroxidation (P < 0.001) SOD and CAT (P < 0.001) was observed in the tissue of OSCC patients as compared with the healthy controls. On the other hand, reduced GSH and GPx were significantly increased in tumor samples. Reduced lipid peroxidation and increased activity of reduced GSH and GPx provides the suitable environment for the local growth and invasion of the tumor and metastasis in the later stages. Among the antioxidant enzymes, GSH reductase appears to have a profound role in carcinogenesis and thus it can be considered as potential prognostic marker.


Association between HLA rs3129882 polymorphism and Parkinson's disease: a meta-analysis.
As one of potential candidate genes for the risk of Parkinson's disease (PD), the HLA-DRA/PARK18 (rs3129882, A > G) gene has been studied extensively. However, direct evidence for the genetic association studies between PD and rs3129882 remains inconclusive. The aim of our meta-analysis was to determine a more reliable association between the rs3129882 and PD. Comprehensive search strategy was used for electronic searches through PubMed, Elsevier, Springer Link, CNKI (Chinese National Knowledge Infrastructure) and WanFang (Chinese) databases to evaluate the association between rs3129882 and PD risk. Data were extracted and the odd ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Finally, we performed a meta-analysis of 13 appropriate papers by using a total of 11951 patients and 11902 controls. The meta-analysis showed no significant association between rs3129882 and PD risk in all four models (the allele model, dominant model, homozygote model and the recessive model). In allele model, the result was OR = 1.043 (95% CI = 0.978, 1.113). Moreover, this association remained no significant in the subgroup analysis stratified by ethnicity. In current meta-analysis, no significant association was found for rs3129882 and PD risk. And more well-designed primary researches will be needed to further evaluate the interaction of rs3129882 polymorphism and the susceptibility of PD.


Health State Utilities for Patients with Brain Metastases.
Estimating the cost-effectiveness of whole-brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS), including Gamma Knife radiosurgery (GKRS), requires the quantitative measurement of patients' health states after treatment. We sought to quantify individuals' preferences for the relevant health states after WBRT or GKRS for brain metastases on a 0 to 1 scale, where 1 is perfect health and 0 is death. We prospectively measured utilities in patients with brain metastases evaluated at Yale for consideration of WBRT and/or GKRS, as well as oncology nurses who had cared for patients with brain metastases before and after WBRT or GKRS, using the Standard Gamble (SG) technique. Demographic information was also collected. Nonparametric tests were used to compare potential differences in utility values and for subgroups based on demographic characteristics. There were 24 patients and 31 nurses who completed the study between December 2013 and May 2015. Median utilities ranged from 0.85 for the status-post (S/P) GKRS state to 0.25 (for neurologic dying). The median utility of being S/P WBRT was 0.70 compared to 0.85 S/P GKRS (p < 0.001). The cognitive decline from WBRT was associated with a notably low utility score of 0.30. There were no statistically significant differences between patients' and nurses' median utility scores. These SG utilities provide unique insights into brain metastases-related health states from the patient and provider perspective. As perceived by individuals with direct knowledge of the health states in question, WBRT has a significantly lower utility compared to GKRS. Cognitive decline following WBRT is associated with significant perceived reduction in quality of life. Differences in the relative importance of overall survival and quality of life with treatment existed between patients with different stages of disease. These utilities can be used to calculate quality-adjusted life expectancy in cost-effectiveness evaluations of SRS and WBRT.


Decreased mivacurium infusion rate and delayed neuromuscular recovery after metoclopramide: a randomized double blind placebo-controlled study.
Metoclopramide is an antiemetic drug which inhibits plasma cholinesterase activity. We have compared the mivacurium infusion requirements and neuromuscular recovery after administration of metoclopramide to a group of adults compared to a control group. Forty-five patients were randomized into three groups. Two groups received either 10 or 20 mg of intravenous (i.v.) metoclopramide and the third group received i.v. saline. Metoclopramide and saline were given 5 min before i.v. induction of anaesthesia. Plasma cholinesterase activity was measured before induction and 30 min after metoclopramide or saline injection. Neuromuscular block was monitored by accelerography using single and train-of-four (TOF) stimulation. The mivacurium intubation dose was followed by an infusion titrated every 5 min to maintain 95% block until the end of surgery when the infusion was stopped. Recovery from mivacurium was then monitored until complete. Mivacurium infusion rates were significantly lower in the metoclopramide groups. After 45 min of infusion, the infusion rates were 1.82 +/- 0.8 and 2.1 +/- 1 microg kg(-1) min(-1) in the 20 and 10 mg metoclopramide groups, respectively, and 6.8 +/- 2.7 in the saline group. Time to recovery of TOF to greater than 90% was significantly prolonged in both metoclopramide groups compared to the saline group: 33.2 +/- 7.2 and 29.5 +/- 10.3 min in the metoclopramide 20 and 10 mg groups, respectively, compared to 22 +/- 3.9 in the saline group (P < 0.001 for the 20 mg group compared to control). Metoclopramide enhances the effect of a mivacurium infusion.


Methods for cultivation of luminal parasitic protists of clinical importance.
Cultivation of luminal protistan parasites has a long history. In this review we discuss the methods and media that are most widely used for the establishment and maintenance of the following organisms in culture: Entamoeba histolytica, Giardia intestinalis, Trichomonas vaginalis, Dientamoeba fragilis, Blastocystis hominis, and Balantidium coli. While cultivation is of limited importance in the diagnostic laboratory, it is essential to most research laboratories, and it is toward the latter that this review is primarily aimed.


Vaccination in the person with newly diagnosed HIV.
People living with human immunodeficiency virus (HIV) are at increased risk of acquiring multiple infections, many of which are preventable by vaccination. When an individual is newly diagnosed with HIV, it is important to take a vaccination history, test for immunity against a range of infectious diseases and administer vaccines as indicated, keeping in mind the person's immune status, as this may affect response to the vaccine, number of recommended doses and timing. This aim of this article is to guide the general practitioner (GP) through each vaccine-preventable disease, highlight the risk in someone newly diagnosed with HIV and discuss the recommended number of doses and optimal timing of administration in relation to the individual's level of immunosuppression. The GP plays an important role in testing and diagnosing individuals with HIV. Prevention of disease is always preferable to treatment, and this article outlines an approach to vaccination that takes into account the variation in the level of immunosuppression that may be present at diagnosis and therefore affect an individual's responsiveness to a standard vaccine schedule.


The circadian deadenylase Nocturnin is necessary for stabilization of the iNOS mRNA in mice.
Nocturnin is a member of the CCR4 deadenylase family, and its expression is under circadian control with peak levels at night. Because it can remove poly(A) tails from mRNAs, it is presumed to play a role in post-transcriptional control of circadian gene expression, but its target mRNAs are not known. Here we demonstrate that Nocturnin expression is acutely induced by the endotoxin lipopolysaccharide (LPS). Mouse embryo fibroblasts (MEFs) lacking Nocturnin exhibit normal patterns of acute induction of TNFα and iNOS mRNAs during the first three hours following LPS treatment, but by 24 hours, while TNFα mRNA levels are indistinguishable from WT cells, iNOS message is significantly reduced 20-fold. Accordingly, analysis of the stability of the mRNAs showed that loss of Nocturnin causes a significant decrease in the half-life of the iNOS mRNA (t(1/2) = 3.3 hours in Nocturnin knockout MEFs vs. 12.4 hours in wild type MEFs), while having no effect on the TNFα message. Furthermore, mice lacking Nocturnin lose the normal nighttime peak of hepatic iNOS mRNA, and have improved survival following LPS injection. These data suggest that Nocturnin has a novel stabilizing activity that plays an important role in the circadian response to inflammatory signals.


Magnetic resonance-guided focused ultrasound of uterine leiomyomas: review of a 12-month outcome of 130 clinical patients.
To assess 12-month outcomes and safety of clinical magnetic resonance (MR)-guided focused ultrasound (US) treatments of uterine leiomyomas. Between March 2005 and December 2009, 150 women with symptomatic uterine leiomyomas were clinically treated with MR-guided focused US at a single institution; 130 patients completed treatment and agreed to have their data used for research purposes. Patients were followed through retrospective review of medical records and phone interviews conducted at 3-, 6-, and 12-month intervals after treatment to assess additional procedures and symptom relief. Outcome measures and treatment complications were analyzed for possible correlations with the appearance of the tumors on T2-weighted imaging. The cumulative incidence of additional tumor-related treatments 12 months after MR-guided focused US was 7.4% by the Kaplan-Meier method. At 3-, 6-, and 12-month follow-up, 86% (90 of 105), 93% (92 of 99), and 88% (78 of 89) of patients reported relief of symptoms, respectively. No statistically significant correlation between tumor appearance on T2-weighted imaging and 12-month outcome was found. Treatment-related complications were observed in 17 patients (13.1%): 16 patients had minor complications and one had a major complication (deep vein thrombosis). All complications were resolved within the 12-month follow-up period. MR-guided focused US is a noninvasive treatment option that can be used to effectively and safely treat uterine leiomyomas and delivers significant and lasting symptom relief for at least 12 months. The incidence of additional treatment during this time period is comparable with those in previous reports of uterine artery embolization.


Meta-analysis reveals glucocorticoid levels reflect variation in metabolic rate, not 'stress'.
Glucocorticoid (GC) variation has long been thought to reflect variation in organismal 'stress,' but associations between GCs and Darwinian fitness components are diverse in magnitude, direction, and highly context-dependent. This paradox reveals our poor understanding of the causes of GC variation, contrasting with the detailed knowledge of the functional consequences of GC variation. Amongst an array of effects in many physiological systems, GCs orchestrate energy availability to anticipate and recover from predictable and unpredictable environmental fluctuations and challenges. Although this is mechanistically well-known, the extent to which GC levels are quantitatively explained by energy metabolism is unresolved. We investigated this association through meta-analysis, selecting studies of endotherms in which (1) an experiment was performed that affected metabolic rate and (2) metabolic rate and GC levels were measured simultaneously. We found that an increase in metabolic rate was associated with an increase in GC levels in 20 out of 21 studies (32 out of 35 effect sizes). More importantly, there was a strong positive correlation between the increases in metabolic rate and GCs (p=0.003). This pattern was similar in birds and mammals, and independent of the nature of the experimental treatment. We conclude that metabolic rate is a major driver of GC variation within individuals. Stressors often affect metabolic rate, leading us to question whether GC levels provide information on 'stress' beyond the stressor's effect on metabolic rate.


Monoclonal antibody treatments for multiple sclerosis.
Monoclonal antibodies (MAbs) may have great potential as therapies for autoimmune diseases. Their development as treatments for multiple sclerosis (MS) is promising. Partially effective immunomodulatory therapies have been helpful for many MS patients; however, for patients failing these immunomodulatory treatments, MAbs are an important new treatment option. Currently, MAbs are approved by the US Food and Drug Administration for treatment of many conditions, including autoimmune diseases. Four MAbs that have been investigated as potential treatments for MS are reviewed in this article. Of these MAbs, natalizumab is approved for treatment of MS. The other three MAbs (alemtuzumab, rituximab, and daclizumab) are all promising therapies in development for treatment of MS. Adverse effects are relatively mild for these MAbs; however, care in administration and management of these agents is emphasized. Overall, these MAb therapies have great promise in the treatment of MS.


Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis.
Topical application of coal tar is one of the oldest therapies for atopic dermatitis (AD), a T helper 2 (Th2) lymphocyte-mediated skin disease associated with loss-of-function mutations in the skin barrier gene, filaggrin (FLG). Despite its longstanding clinical use and efficacy, the molecular mechanism of coal tar therapy is unknown. Using organotypic skin models with primary keratinocytes from AD patients and controls, we found that coal tar activated the aryl hydrocarbon receptor (AHR), resulting in induction of epidermal differentiation. AHR knockdown by siRNA completely abrogated this effect. Coal tar restored filaggrin expression in FLG-haploinsufficient keratinocytes to wild-type levels, and counteracted Th2 cytokine-mediated downregulation of skin barrier proteins. In AD patients, coal tar completely restored expression of major skin barrier proteins, including filaggrin. Using organotypic skin models stimulated with Th2 cytokines IL-4 and IL-13, we found coal tar to diminish spongiosis, apoptosis, and CCL26 expression, all AD hallmarks. Coal tar interfered with Th2 cytokine signaling via dephosphorylation of STAT6, most likely due to AHR-regulated activation of the NRF2 antioxidative stress pathway. The therapeutic effect of AHR activation herein described opens a new avenue to reconsider AHR as a pharmacological target and could lead to the development of mechanism-based drugs for AD.


Familial components of the multiple metabolic syndrome: the ARIC study.
The association of a parental history of diabetes mellitus and hypertension with the multiple metabolic syndrome (MMS) was studied in a population survey of middle-aged adults. The eligible population was drawn from the baseline examination of the Atherosclerosis Risk in Communities Study, a population-based, bi-ethnic, multi-centre cohort study. The MMS was defined as a multivariate, categorical phenotype of co-occurring diabetes, hypertension, and dyslipidaemia. MMS cases (n = 356) were compared to disorder-free control subjects (n = 6797) with respect to their parental history of diabetes and hypertension. MMS cases were more likely to report a history of diabetes in both parents (odds ratio [OR] 4.7, 95 % confidence interval (CI) 1.5-14.7) or a history of hypertension in both parents (OR 1.9, 95 % CI 1.1-3.0) than control subjects, adjusting for BMI, waist-to-hip ratio, age, gender, and ethnicity/centre. A parental history of diabetes and hypertension in both parents was associated with the greatest increase in odds of MMS (OR 8.3, 95 % CI 3.0-22.8). A dose-response relationship between the number of parental disorders (one; two; three to four) and the odds of MMS was observed (OR 1.2, 95 % CI 0.9-1.7; OR 2.0, 95 % CI 1.4-2.8; OR 4.0, 95 % CI 2.5-6.2). Based on the marked associations observed between a parental history of MMS components and the clustering of these metabolic disorders in the offspring generation, we conclude that genetic and/or non-genetic familial influences play a role in the development of the multiple metabolic syndrome.


Brain tumor stem cell multipotency correlates with nanog expression and extent of passaging in human glioblastoma xenografts.
Glioblastoma multiforme (GBM) is the most common primary brain tumor, with a median survival of only 15 months. A subpopulation of cells, the brain tumor stem cells (BTSCs), may be responsible for the malignancy of this disease. Xenografts have proven to be a robust model of human BTSCs, but the effects of long-term passaging have yet to be determined. Here we present a study detailing changes in BTSC multipotency, invasive migration, and proliferation after serial passaging of human GBM xenografts. Immunocytochemistry and tumorsphere formation assays demonstrated the presence of BTSCs in both early generation (EG-BTSCs; less than 15 passages) and late generation (LG-BTSCs; more than 24 passages) xenografts. The EG-BTSCs upregulated expression of lineage markers for neurons and oligodendrocytes upon differentiation, indicating multipotency. In contrast, the LG-BTSCs were restricted to an astrocytic differentiation. Quantitative migration and proliferation assays showed that EG-BTSCs are more migratory and proliferative than LG-BTSCs. However, both populations respond similarly to the chemokine SDF-1 by increasing invasive migration. These differences between the EG- and LG-BTSCs were correlated with a significant decrease in nanog expression as determined by qRT-PCR. Mice implanted intracranially with EG-BTSCs showed shorter survival when compared to LG-BTSCs. Moreover, differentiation prior to implantation of EG-BTSCs, but not LG-BTSCs, led to increased survival. Thus, nanog may identify multipotent BTSCs. Furthermore, limited passaging of xenografts preserves these multipotent BTSCs, which may be an essential underlying feature of GBM lethality.


Diagnostics in Patients Suspect for Breast Cancer in The Netherlands.
The goal of this study was to describe the variation in hospital-based diagnostic care activities for patients with symptomatology suspect for breast cancer in The Netherlands. Two cohorts were included: the 'benign' cohort (30,334 women suspected of, but without breast cancer) and the 'malignant' cohort (2236 breast cancer patients). Hospital-based financial data was combined with tumor data (malignant cohort) from The Netherlands Cancer Registry. Patterns within diagnostic pathways were analyzed. Factors influencing the number of visits and number of diagnostic care activities until diagnosis were identified in the malignant cohort with multivariable Cox and Poisson regression models. Compared to patients with benign diagnosis, patients with malignant disease received their diagnosis less frequently in one day, after an equal average number of hospital visits and higher average number of diagnostic activities. Factors increasing the number of diagnostic care activities were the following: lower age and higher cM-and cN-stages. Factors increasing the number of days until (malignant) diagnosis were as follows: higher BIRADS-score, screen-detected and higher cN-and cT-stages. Hospital of diagnosis influenced both number of activities and days to diagnosis. The diagnostic care pathway of patients with malignant disease required more time and diagnostic activities than benign disease and depends on hospital, tumor and patient characteristics.


L-arginine supplementation attenuates ovarian oxidative stress in female rats subjected to chronic intermittent hypoxia.
Systemic and organ-specific oxidative stress triggered by hypoxia is suggested to play a key role in germ cell apoptosis and DNA damage. This study was designed to investigate the impact of chronic intermittent hypoxia (CIH) on female fertility and evaluate the potential antioxidant effect of L-arginine (L-Arg) supplementation. Adult female rats were allocated into three groups: controls (normoxic), hypoxic and hypoxic supplemented with L-Arg. After 12 weeks; hematocrit value was determined, body weight (BW) and ovarian weight were measured for the calculation of the gonado-somatic index. Plasma levels of luteinizing hormone (LH) and progesterone were estimated. Ovarian tissue malondialdehyde (MDA) and catalase were assessed, and caspase-3 enzyme expression was detected by immunohistochemistry. Compared to controls, CIH resulted in increased oxidative stress in the ovarian tissue, decreased ovarian weight, and increased frequency of irregular cycles and higher plasma level of LH in rats with either regular or irregular ovarian cycles. Histological examination of ovarian sections revealed areas of degeneration, atretic follicles, interstitial edema, congested vessels and inflammatory cell infiltration. Immunohistochemistry confirmed the presence of apoptosis by increased caspase-3 expression. Hypoxic rats pre-treated with L-Arg showed increased BW and ovarian weight, decreased ovarian tissue MDA and plasma LH accompanied by a lower incidence of irregular cycles and mortality. The histological picture was improved and caspase-3 expression was reduced. Oxidative stress caused by CIH is detrimental to the structure and function of the corpus luteum with an increased risk of reduced fertility. L-Arg supplementation increases antioxidant capacity and improves hypoxia-induced fertility disorders.


Calculating the Partition Coefficients of Organic Solvents in Octanol/Water and Octanol/Air.
Partition coefficients define how a solute is distributed between two immiscible phases at equilibrium. The experimental estimation of partition coefficients in a complex system can be an expensive, difficult, and time-consuming process. Here a computational strategy to predict the distributions of a set of solutes in two relevant phase equilibria is presented. The octanol/water and octanol/air partition coefficients are predicted for a group of polar solvents using density functional theory (DFT) calculations in combination with a solvation model based on density (SMD) and are in excellent agreement with experimental data. Thus, the use of quantum-chemical calculations to predict partition coefficients from free energies should be a valuable alternative for unknown solvents. The obtained results indicate that the SMD continuum model in conjunction with any of the three DFT functionals (B3LYP, M06-2X, and M11) agrees with the observed experimental values. The highest correlation to experimental data for the octanol/water partition coefficients was reached by the M11 functional; for the octanol/air partition coefficient, the M06-2X functional yielded the best performance. To the best of our knowledge, this is the first computational approach for the prediction of octanol/air partition coefficients by DFT calculations, which has remarkable accuracy and precision.


Parental effects on embryonic viability and growth in Arctic charr Salvelinus alpinus at two incubation temperatures.
The parental influences on three progeny traits (survival to eyed-embryo stage, post-hatching body length and yolk-sac volume) of Arctic charr Salvelinus alpinus were studied under two thermal conditions (2 and 7 degrees C) using a factorial mating design. The higher temperature resulted in elevated mortality rates and less advanced development at hatching. Survival was mostly attributable to maternal effects at both temperatures, but the variation among families was dependent on egg size only at the low temperature. No additive genetic variation (or pure sire effect) could be observed, whereas the non-additive genetic effects (parental combination) contributed to offspring viability at 2 degrees C. In contrast, any observable genetic variance in survival was lost at 7 degrees C, most likely due to the increased environmental variance. Irrespective of temperature, dam and sire-dam interaction contributed significantly to the phenotypic variation in both larval length and yolk size. A significant proportion of the variation in larval length was also due to the sire effect at 2 degrees C. Maternal effects were mediated partly through egg size, but as a whole, they decreased in importance at the high temperature, enabling a concomitant increase in non-additive genetic effects. For larval length, however, the additive component, like maternal effects, decreased at 7 degrees C. The present results suggest that an exposure to thermal stress during incubation can modify the genetic architecture of early developmental traits in S. alpinus and presumably constrain their short-term adaptive potential and evolvability by increasing the amount of environmentally induced variation.


How and where clinicians exercise power: interprofessional relations in health care.
This study aims to contribute to the limited set of interactional studies of health occupational relations. A "negotiated order" perspective was applied to a multi-site setting to articulate the ways in which clinicians' roles, accountabilities and contributions to patient care are shaped by the care setting and are influenced by the management of patient pathways. The study responds to the polarized debate between a critical perspective that calls for collaboration as the re-distribution of occupational power, and a functionalist view that argues for better coordination of health care teams. The study draws on data from 63 interviews, 68 focus groups and 209 h of observation across acute and non-acute health services within a state/territory in Australia. The paper reveals the exercise of both "competitive power" and "collaborative power" in the negotiated order of health services. Both forms of power are exercised in all settings. Relationships among clinicians in various occupations are mediated by the expectation that doctors assume responsibility for patient management and coordinating roles in health care teams, and the degree of acuity of particular health care settings. The combination of a negotiated order perspective and its unique application across a whole health system shows the continuation of a broad pattern of power by doctors over those in other roles. The paper also reveals novel criteria for evaluating the extent of power-sharing in interprofessional interaction in case conferences, and a unique quantification of such interaction.


Potentially inappropriate prescribing in older adults with advanced chronic kidney disease.
Older adults with chronic kidney disease (CKD) are at heightened risk for polypharmacy. We examined potentially inappropriate prescribing in this population and whether introducing pharmacists into the ambulatory kidney care model was associated with improved prescribing practices. Retrospective cohort study using linked administrative databases. We included patients with an eGFR ≤30 mL/min/1.73 m2 ≥66 years of age followed in multidisciplinary kidney clinics in Ontario, Canada (n = 25,016 from 28 centres). The primary outcome was the absence of a statin prescription or the receipt of a potentially inappropriate prescription defined by the American Geriatric Society Beers Criteria® and a modified Delphi panel that identified key drugs of concern in CKD. We calculated the crude cumulative incidence and incidence rate for the primary outcome and used change-point regression to determine if a change occurred following pharmacist introduction. There were 6,007 (24%) and 16,497 patients (66%) not prescribed a statin and with ≥1 potentially inappropriate prescription, respectively. The rate of potentially inappropriate prescribing was 125.6 per 100 person-years and was higher in more recent years. The change-point regression analysis included 2,275 patients from two centres. No immediate change was detected at pharmacist introduction, but potentially inappropriate prescribing was increasing pre-pharmacist introduction, and this rising trend was reversed post-pharmacist introduction. The incidence of potentially inappropriate prescribing still remained high post-pharmacist introduction. Potentially inappropriate prescribing practices were common. Incorporating pharmacists into the kidney care model may improve prescribing practices. The role of pharmacists in the ambulatory kidney care team warrants further investigation in a randomized controlled trial.


Acute morphine induces matrix metalloproteinase-9 up-regulation in primary sensory neurons to mask opioid-induced analgesia in mice.
Despite decades of intense research efforts, actions of acute opioids are not fully understood. Increasing evidence suggests that in addition to well-documented antinociceptive effects opioids also produce paradoxical hyperalgesic and excitatory effects on neurons. However, most studies focus on the pronociceptive actions of chronic opioid exposure. Matrix metalloproteinase 9 (MMP-9) plays an important role in neuroinflammation and neuropathic pain development. We examined MMP-9 expression and localization in dorsal root ganglia (DRGs) after acute morphine treatment and, furthermore, the role of MMP-9 in modulating acute morphine-induced analgesia and hyperalgesia in mice. Subcutaneous morphine induced a marked up-regulation of MMP-9 protein in DRGs but not spinal cords. Morphine also increased MMP-9 activity and mRNA expression in DRGs. MMP-9 up-regulation peaked at 2 h but returned to the baseline after 24 h. In DRG tissue sections, MMP-9 is expressed in small and medium-sized neurons that co-express mu opioid receptors (MOR). In DRG cultures, MOR agonists morphine, DAMGO, and remifentanil each increased MMP-9 expression in neurons, whereas the opioid receptor antagonist naloxone and the MOR-selective antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂ (CTAP) suppressed morphine-induced MMP-9 expression. Notably, subcutaneous morphine-induced analgesia was enhanced and prolonged in Mmp9 knockout mice and also potentiated in wild-type mice receiving intrathecal injection of MMP-9 inhibitors. Consistently, intrathecal injection of specific siRNA targeting MMP-9 reduced MMP-9 expression in DRGs and enhanced and prolonged morphine analgesia. Subcutaneous morphine also produced heat hyperalgesia at 24 h, but this opioid-induced hyperalgesia was not enhanced after MMP-9 deletion or inhibition. Transient MMP-9 up-regulation in DRG neurons can mask opioid analgesia, without modulating opioid-induced hyperalgesia. Distinct molecular mechanisms (MMP-9 dependent and independent) control acute opioid-induced pronociceptive actions (anti-analgesia in the first several hours and hyperalgesia after 24 h). Targeting MMP-9 may improve acute opioid analgesia.


Stabilizing the iterative solution to ultrasonic transmission tomography.
A stable iterative reconstruction algorithm is presented for ultrasonic tomography through the uses of weighting matrices, damping factor, and the features of conjugate gradient method. The weighting matrices are chosen according to Berryman's analysis of nonlinear tomography. An implicit conjugate gradient-type iterative formula is used to solve a weighted least-squares problem. In the iterative process, a damping factor of linear increase rather than a constant is used to filter out the influences of smaller singular values' components. The results of simulated data show that our method can efficiently stabilize the iteration, and provide a robust solution.


Thermometry and calorimetry assessment of sweat response during exercise in the heat.
Our objective was to characterise sweat rate responses in a hot environment during rest and subsequent increasing levels of exercise in relation to thermometrically (i.e., rectal, tympanic, mean skin and mean body temperatures) and calorimetrically derived (i.e., change in body heat storage) thermal parameters. Ten healthy males volunteered and entered an environmental chamber set at 42 degrees C. Participants rested seated during their first hour inside the chamber. Thereafter, they exercised to volitional exhaustion on a cycle ergometer at 20 W with step increments of 20 W h(-1). Across time, fluctuations in sweat rate were systematically associated with similar fluctuations in the integral of body heat storage (t = 13.16, P < 0.001), but not rectal (t = 0.98, P > 0.05), tympanic (t = 0.81, P > 0.05), mean skin (t = 0.12, P > 0.05), or mean body (t = 0.93, P > 0.05) temperatures. In addition, 95% limits of agreement and regression analyses showed that the changes in sweat rate demonstrated the highest agreement and strongest associations with changes in the integral of body heat storage. It is concluded that in a hot environment during rest and subsequent increasing levels of exercise sweat rate is associated with the cumulative changes in the rate of body heat storage.


Survival among people hospitalized with COVID-19 in Switzerland: a nationwide population-based analysis.
Increasing age, male sex, and pre-existing comorbidities are associated with lower survival from SARS-CoV-2 infection. The interplay between different comorbidities, age, and sex is not fully understood, and it remains unclear if survival decreases linearly with higher ICU occupancy or if there is a threshold beyond which survival falls. This national population-based study included 22,648 people who tested positive for SARS-CoV-2 infection and were hospitalized in Switzerland between February 24, 2020, and March 01, 2021. Bayesian survival models were used to estimate survival after positive SARS-CoV-2 test among people hospitalized with COVID-19 by epidemic wave, age, sex, comorbidities, and ICU occupancy. Two-way interactions between age, sex, and comorbidities were included to assess the differential risk of death across strata. ICU occupancy was modeled using restricted cubic splines to allow for a non-linear association with survival. Of 22,648 people hospitalized with COVID-19, 4785 (21.1%) died. The survival was lower during the first epidemic wave than in the second (predicted survival at 40 days after positive test 76.1 versus 80.5%). During the second epidemic wave, occupancy among all available ICU beds in Switzerland varied between 51.7 and 78.8%. The estimated survival was stable at approximately 81.5% when ICU occupancy was below 70%, but worse when ICU occupancy exceeded this threshold (survival at 80% ICU occupancy: 78.2%; 95% credible interval [CrI] 76.1 to 80.1%). Periods with higher ICU occupancy (>70 vs 70%) were associated with an estimated number of 137 (95% CrI 27 to 242) excess deaths. Comorbid conditions reduced survival more in younger people than in older people. Among comorbid conditions, hypertension and obesity were not associated with poorer survival. Hypertension appeared to decrease survival in combination with cardiovascular disease. Survival after hospitalization with COVID-19 has improved over time, consistent with improved management of severe COVID-19. The decreased survival above 70% national ICU occupancy supports the need to introduce measures for prevention and control of SARS-CoV-2 transmission in the population well before ICUs are full.


Nuclear RNAs confined to a reticular compartment between chromosome territories.
RNA polymerase II transcripts are confined to nuclear compartments. A detailed analysis of the nuclear topology of RNA from individual genes was performed for transcripts from the marker gene coding for chloramphenicol acetyltransferase, expressed at a high level from the HTLV-1 LTR promoter. The construct was transfected into A293 cells where the RNA was organized as an extensive reticular network. We also studied the RNA distribution from combinations of neighboring HIV and bacterial resistance genes that co-integrated within the genome of COS-7 cells-revealing spherical or track-like accumulations of RNA that were extensively branched. There were many nuclei with distinct but overlapping RNA accumulations. Since the coding genes localized at the overlapping points, the RNAs are synthesized at a common region and diverge. The correlation between the frequency of the separation of the transcripts and the physical distance of the respective genes suggests a subcompartmentalization in the microenvironment of genes on the basis of geometric parameters. Thus, the more distant the genes are on the same chromosome, the more likely they are confined to separated subcompartments of an extensive reticular system. Co-delineation of the RNA transcripts with Cajal bodies and chromosome territories indicated the organization of nuclear RNA transcripts in a reticular interchromosome domain compartment.


Non-invasive evaluation of hemodynamics in pulmonary hypertension by a Septal angle measured by computed tomography pulmonary angiography: Comparison with right-heart catheterization and association with N-terminal pro-B-type natriuretic peptide.
The septal angle, an angle between the interventricular septum and the line connecting the sternum midpoint and thoracic vertebral spinous process, as measured by computed tomographic pulmonary angiography (CTPA), has been observed to be increased in patients with pulmonary hypertension (PH), but its meaning remains unclear. The aim of this study was to investigate the potential role of the septal angle in evaluating hemodynamics and its association with N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with PH. Patients with PH (n=106), including 76 with chronic thromboembolic pulmonary hypertension (CTEPH) and 30 with pulmonary artery hypertension (PAH), were retrospectively reviewed. The patients underwent CTPA prior to right-heart catheterization. The septal angle was measured on transversal CTPA images. Hemodynamic parameters were evaluated by right-heart catheterization. The level of plasma NT-proBNP was measured by enzyme-linked sandwich immunoassay. The septal angle had a moderate correlation with cardiac output (CO; r=-0.535, P=0.000) and a high correlation with pulmonary vascular resistance (PVR; r=0.642, P=0.000). The mean level of NT-proBNP in PH was 1,716.09±1,498.30 pg/ml, which correlated with the septal angle (r=0.693, P=0.000). In a stepwise forward regression analysis, the Septal angle was entered into the final equation for predicting PVR, leading to the following equation: PVR = 28.256 × Septal angle - 728.72. In CTEPH, the Septal angle strongly correlated with NT-proBNP (r=0.668, P=0.000) and PVR (r=0.676, P=0.000). In PAH, the Septal angle strongly correlated with NT-proBNP (r=0.616, P=0.003) and PVR (r=0.623, P=0.000). The CTPA-derived Septal angle is a superior predictor for evaluating and monitoring the level of NT-proBNP and PVR in patients with PH.


Phenotypic and genetic heterogeneity among subjects with mild airflow obstruction in COPDGene.
Chronic obstructive pulmonary disease (COPD) is characterized by marked phenotypic heterogeneity. Most previous studies have focused on COPD subjects with FEV1 < 80% predicted. We investigated the clinical and genetic heterogeneity in subjects with mild airflow limitation in spirometry grade 1 defined by the Global Initiative for chronic Obstructive Lung Disease (GOLD 1). Data from current and former smokers participating in the COPDGene Study (NCT00608764) were analyzed. K-means clustering was performed to explore subtypes within 794 GOLD 1 subjects. For all subjects with GOLD 1 and with each cluster, a genome-wide association study and candidate gene testing were performed using smokers with normal lung function as a control group. Combinations of COPD genome-wide significant single nucleotide polymorphisms (SNPs) were tested for association with FEV1 (% predicted) in GOLD 1 and in a combined group of GOLD 1 and smoking control subjects. K-means clustering of GOLD 1 subjects identified putative "near-normal", "airway-predominant", "emphysema-predominant" and "lowest FEV1% predicted" subtypes. In non-Hispanic whites, the only SNP nominally associated with GOLD 1 status relative to smoking controls was rs7671167 (FAM13A) in logistic regression models with adjustment for age, sex, pack-years of smoking, and genetic ancestry. The emphysema-predominant GOLD 1 cluster was nominally associated with rs7671167 (FAM13A) and rs161976 (BICD1). The lowest FEV1% predicted cluster was nominally associated with rs1980057 (HHIP) and rs1051730 (CHRNA3). Combinations of COPD genome-wide significant SNPs were associated with FEV1 (% predicted) in a combined group of GOLD 1 and smoking control subjects. Our results indicate that GOLD 1 subjects show substantial clinical heterogeneity, which is at least partially related to genetic heterogeneity.


[Study of gelatin hydrolysis by Streptomyces griseus protease using the method of N-terminal analysis].
The ariticle deals with gelatin hydrolysis by the crystalline preparation of the Str. griseus protease. 12.1% of 1080 peptide bonds available in 105 g of protein split for 24 h at 40 C. The bonds of 8-9 types which involve N-end of glycine, serine, phenylalanine, threonine, leucine, valine, glutaminic acid, lysine break at once. The process occurs with delay, and 0.25, 0.5, 6 and 24 h after there occurs a breakage of the 42d, 61st, 117th and131st bonds. The middle size of the peptide chain of the initial protein is 604 amino acid residues, in the hydrolyzate 30, 22, 11.6 and 11.3 residues are found within these intervals, respectively. Main changes occur in the fraction of soluble peptides where number of N-terminal amino acids rises from 25 to 80. Some data are obtained on the total specificity of the Str. griseus protease. It splits mostly the bonds which involve the N-end of glycine (51%), alanine 2%), serine (9%). The content of the definite amino acid in gelatin shows that hydrolysis bonds of serine and threonine accounts for 35.2 and 35.6%, valine and leucine for 23.6 and 24.7%, glycine and alanine for 18.8 and 13%, methionine, lysine, glutaminic and asparagic acids for 7-9%; the proline bonds are not splitted at all. An assumption is advanced on the presence of four groups of bonds in gelatin; the rate of their hydrolysis corresponding to the enzyme specificity. The Str. griseus protease splits as free amino acids 10 mol of serine of 35,5, 5.5 mol of leucine of 26.3, 3.6 mol of threonine of 19.8 and only 4 mol of glycine of 363 available in gelatin.


Functional inactivation of the genome-wide association study obesity gene neuronal growth regulator 1 in mice causes a body mass phenotype.
To date, genome-wide association studies (GWAS) have identified at least 32 novel loci for obesity and body mass-related traits. However, the causal genetic variant and molecular mechanisms of specific susceptibility genes in relation to obesity are yet to be fully confirmed and characterised. Here, we examined whether the candidate gene NEGR1 encoding the neuronal growth regulator 1, also termed neurotractin or Kilon, accounts for the obesity association. To characterise the function of NEGR1 for body weight control in vivo, we generated two novel mutant mouse lines, including a constitutive NEGR1-deficient mouse line as well as an ENU-mutagenised line carrying a loss-of-function mutation (Negr1-I87N) and performed metabolic phenotypic analyses. Ablation of NEGR1 results in a small but steady reduction of body mass in both mutant lines, accompanied with a small reduction in body length in the Negr1-I87N mutants. Magnetic resonance scanning reveals that the reduction of body mass in Negr1-I87N mice is due to a reduced proportion of lean mass. Negr1-I87N mutants display reduced food intake and physical activity while normalised energy expenditure remains unchanged. Expression analyses confirmed the brain-specific distribution of NEGR1 including strong expression in the hypothalamus. In vitro assays show that NEGR1 promotes cell-cell adhesion and neurite growth of hypothalamic neurons. Our results indicate a role of NEGR1 in the control of body weight and food intake. This study provides evidence that supports the link of the GWAS candidate gene NEGR1 with body weight control.


Quantitation of glyphosate, glufosinate, and AMPA in drinking water and surface waters using direct injection and charged-surface chromatography coupled to ultra-high performance liquid chromatography-tandem mass spectrometry.
Herbicides glyphosate (N-(phosphonomethyl)glycine) and glufosinate (2-amino-4-(hydroxymethylphosphinyl)butanoic acid) and the main transformation product of glyphosate, aminomethanephosphonic acid (AMPA), are challenging to analyze for in environmental samples. The quantitative method developed by this study adapts previously standardized dechlorination procedures coupled to a novel charged surface C18 column, ultra-high performance liquid chromatography-tandem mass spectrometry, polarity switching, and direct injection. The method was applied to chlorinated tap water, as well as river samples, collected in the City of Winnipeg and rural Manitoba, Canada. Using only syringe filtration without derivatization, the validated method resulted in good accuracies in both tap and surface water, at both 2 and 20 μg L-1. Method limits of detection (MLD) and quantification (MLQ) ranged from 0.022/0.074 to 0.11/0.36 μg L-1, with precisions of 0.46-2.2% (intraday) and 1.3-7.3% (interday). The mean (SEM) of the pesticides in μg L-1 for tap water were 0.11 (0.007) (AMPA), glufosinate and glyphosate < MLDs; and for Red River water were 0.56 (0.045) (AMPA), glufosinate < MLQ, and glyphosate 0.40 (0.072). For the smaller tributaries, glufosinate was >MLD but < MLQ once and that was for Shannon Creek at 0.2 μg L-1. For the remaining rivers, the mean concentrations ranged from 0.31 to 3.1 μg L-1 for AMPA, and 0.087-0.53 μg L-1 for glyphosate. The method will be ideal for supporting monitoring and risk assessment programs that require high throughput sampling and quantitative methods capable of producing robust results that leverages chromatographic and mass spectrometric paradigms instead of being extraction technology focused.


Dendritic cells are responsible for the capacity of CpG oligodeoxynucleotides to act as an adjuvant for protective vaccine immunity against Leishmania major in mice.
Vaccination with leishmanial Ag and CpG oligodeoxynucleotides (ODN) confers sustained cellular immunity and protection to infectious challenge up to 6 mo after immunization. To define the cellular mechanism by which CpG ODN mediate their adjuvant effects in vivo, the functional capacity of distinct dendritic cell (DC) subsets was assessed in the lymph nodes (LNs) of BALB/c mice, 36 h after immunization with the leishmanial antigen (LACK) and CpG ODN. After this immunization, there was a striking decrease in the frequency of the CD11c+B220+ plasmacytoid DCs with a proportionate increase in CD11c+CD8-B220- cells. CD11c+CD8+B220- cells were the most potent producers of interleukin (IL)-12 p70 and interferon (IFN)-gamma, while plasmacytoid DCs were the only subset capable of secreting IFN-alpha. In terms of antigen presenting capacity, plasmacytoid DCs were far less efficient compared with the other DC subsets. To certify that DCs were responsible for effective vaccination, we isolated CD11c+ and CD11c- cells 36 h after immunization and used such cells to elicit protective immunity after adoptive transfer in naive, Leishmania major susceptible BALB/c mice. CD11c+ cells but not 10-fold higher numbers of CD11c- cells from such immunized mice mediated protection. Therefore, the combination of LACK antigen and CpG ODN adjuvant leads to the presence of CD11c+ DCs in the draining LN that are capable of vaccinating naive mice in the absence of further antigen or adjuvant.


[Bactericidal properties of hemo-cytolysin from Vibrio cholerae non O1 P-11702 strain in a panel of indicator cultures for detection of vibriocins].
The influence of the preparation of hemo-cytolysin, obtained from V. cholerae non O1 strain P-11702 and inducing lysis of both red blood cells and V. cholerae cultures using a panel of indicator cultures for the detection of vibriocins, was studied. The set of indicator cultures contained 2 Shigella flexneri strains, 1 S. dysenteriae strain, 3 S. sonnei strains, 3 Escherichia coli strains and 2 V. cholerae strains, one of them being atypical. Hemo-cytolysin exhibited lytic activity with respect to S. dysenteriae, S. sonnei strains and 1 V. cholerae strain. i.e. to 4 out of 11 indicator strains. V. cholerae atypical strain proved to be resistant to the preparation in contrast to 33 V. cholerae typical strains, studied previously.


Molecular signatures in the progression of COVID-19 severity.
SARS-CoV-2 is the causative agent of COVID-19 that has infected over 642 million and killed over 6.6 million people around the globe. Underlying a wide range of clinical manifestations of this disease, from moderate to extremely severe systemic conditions, could be genes or pathways differentially expressing in the hosts. It is therefore important to gain insights into pathways involved in COVID-19 pathogenesis and host defense and thus understand the host response to this pathogen at the physiological and molecular level. To uncover genes and pathways involved in the differential clinical manifestations of this disease, we developed a novel gene co-expression network based pipeline that uses gene expression obtained from different SARS-CoV-2 infected human tissues. We leveraged the network to identify novel genes or pathways that likely differentially express and could be physiologically significant in the COVID-19 pathogenesis and progression but were deemed statistically non-significant and therefore not further investigated in the original studies. Our network-based approach aided in the identification of co-expression modules enriched in differentially expressing genes (DEGs) during different stages of COVID-19 and enabled discovery of novel genes involved in the COVID-19 pathogenesis, by virtue of their transcript abundance and association with genes expressing differentially in modules enriched in DEGs. We further prioritized by considering only those enriched gene modules that have most of their genes differentially expressed, inferred by the original studies or this study, and document here 7 novel genes potentially involved in moderate, 2 in severe, 48 in extremely severe COVID-19, and 96 novel genes involved in the progression of COVID-19 from severe to extremely severe conditions. Our study shines a new light on genes and their networks (modules) that drive the progression of COVID-19 from moderate to extremely severe condition. These findings could aid development of new therapeutics to combat COVID-19.


Significant variability exists in the cytotoxicity of global methicillin-resistant Staphylococcus aureus lineages.
Staphylococcus aureus is a major human pathogen where the emergence of antibiotic resistant lineages, such as methicillin-resistant S. aureus (MRSA), is a major health concern. While some MRSA lineages are restricted to the healthcare setting, the epidemiology of MRSA is changing globally, with the rise of specific lineages causing disease in healthy people in the community. In the past two decades, community-associated MRSA (CA-MRSA) has emerged as a clinically important and virulent pathogen associated with serious skin and soft-tissue infections (SSTI). These infections are primarily cytotoxin driven, leading to the suggestion that hypervirulent lineages/multi-locus sequence types (STs) exist. To examine this, we compared the cytotoxicity of 475 MRSA isolates representing five major MRSA STs (ST22, ST93, ST8, ST239 and ST36) by employing a monocyte-macrophage THP-1 cell line as a surrogate for measuring gross cytotoxicity. We demonstrate that while certain MRSA STs contain highly toxic isolates, there is such variability within lineages to suggest that this aspect of virulence should not be inferred from the genotype of any given isolate. Furthermore, by interrogating the accessory gene regulator (Agr) sequences in this collection we identified several Agr mutations that were associated with reduced cytotoxicity. Interestingly, the majority of isolates that were attenuated in cytotoxin production contained no mutations in the agr locus, indicating a role of other undefined genes in S. aureus toxin regulation.


MicroRNA expression profiling of thymic epithelial tumors.
Thymic epithelial tumors (TET) are the most frequent human primary mediastinal tumors in adults. A deep biological characterization of the processes at the basis of the transformed phenotype could strongly improve our understanding of the morphological and clinical heterogeneity of these diseases. MicroRNAs (miRNAs) are non-coding RNAs involved in post-transcriptional regulation and their altered expression accounts for the pathogenesis of several tumors. The aim of this study was to identify the miRNAs that are differentially expressed in tumor vs normal thymic tissues or among the different tumor histotypes and that could impact on the biology of TET. microRNAs expression profiling was performed by microarray analysis of formalin-fixed paraffin embedded (FFPE) tissue from 54 thymic tumor samples and 12 normal counterparts, derived from two patient cohorts. We identified groups of miRNAs differentially expressed between: (i) TET and normal thymic tissues, (ii) thymomas and thymic carcinomas, (iii) histotype groups. Moreover, we identified putative molecular pathways targeted by these differentially expressed miRNAs that could be involved in thymic carcinogenesis and in the maintenance and spreading of this tumor.


How non-veridical perception drives actions in healthy humans: evidence from synaesthesia.
We continually perform actions that are driven by our perception and it is a commonly held view that only objectively perceived changes within the 'real' world affect behaviour. Exceptions are generally only made for mental health disorders associated with delusions and hallucinations where behaviour may be triggered by the experience of objectively non-existent percepts. Here, we demonstrate, using synaesthesia as a model condition (in N = 19 grapheme-colour synaesthetes), how objectively non-existent (i.e. non-veridical) but still non-pathological perceptions affect actions in healthy humans. Using electroencephalography, we determine whether early-stage perceptual processes (reflected by P1 and N1 event-related potential (ERP) components), or late-stage-integration processes (reflected by N2 component), underlie the effects of non-veridical perceptions on action control. ERP analysis suggests that even though the examined peculiarities and experimental variations are perceptual in nature, it is not early-stage perceptual processes, but rather higher-order executive control processes linking perceptions to the appropriate motor response underlying this effect. Source localization analysis implicates activation within medial frontal cortices in the effect of how irrelevant non-veridical perceptions modulate behaviour. Our results challenge common conceptions about the determinants of human behaviour but can be explained by well-established theoretical frameworks detailing the link between perception and action. This article is part of a discussion meeting issue 'Bridging senses: novel insights from synaesthesia'.


Phylogenetic analysis reveals a high prevalence of Sporothrix brasiliensis in feline sporotrichosis outbreaks.
Sporothrix schenckii, previously assumed to be the sole agent of human and animal sporotrichosis, is in fact a species complex. Recently recognized taxa include S. brasiliensis, S. globosa, S. mexicana, and S. luriei, in addition to S. schenckii sensu stricto. Over the last decades, large epidemics of sporotrichosis occurred in Brazil due to zoonotic transmission, and cats were pointed out as key susceptible hosts. In order to understand the eco-epidemiology of feline sporotrichosis and its role in human sporotrichosis a survey was conducted among symptomatic cats. Prevalence and phylogenetic relationships among feline Sporothrix species were investigated by reconstructing their phylogenetic origin using the calmodulin (CAL) and the translation elongation factor-1 alpha (EF1α) loci in strains originated from Rio de Janeiro (RJ, n = 15), Rio Grande do Sul (RS, n = 10), Paraná (PR, n = 4), São Paulo (SP, n =3) and Minas Gerais (MG, n = 1). Our results showed that S. brasiliensis is highly prevalent among cats (96.9%) with sporotrichosis, while S. schenckii was identified only once. The genotype of Sporothrix from cats was found identical to S. brasiliensis from human sources confirming that the disease is transmitted by cats. Sporothrix brasiliensis presented low genetic diversity compared to its sister taxon S. schenckii. No evidence of recombination in S. brasiliensis was found by split decomposition or PHI-test analysis, suggesting that S. brasiliensis is a clonal species. Strains recovered in states SP, MG and PR share the genotype of the RJ outbreak, different from the RS clone. The occurrence of separate genotypes among strains indicated that the Brazilian S. brasiliensis epidemic has at least two distinct sources. We suggest that cats represent a major host and the main source of cat and human S. brasiliensis infections in Brazil.


Effects of the Intensity and Activity Time of Early Rehabilitation on Activities of Daily Living Dependence in Mechanically Ventilated Patients.
The aim of this study was to investigate the association between the Rehabilitation Activity Time score (RATs)-a score based on the level and duration of rehabilitation activities-of ventilated patients in the intensive care unit (ICU) and activities of daily living (ADL) dependence at discharge. This retrospective, single-center study evaluated patients aged >18 years who underwent mechanical ventilation in the ICU for at least 48 h. The patients were categorized into the low- and high-dose rehabilitation groups based on the median RATs. The primary outcome was the rate of ADL dependence at discharge, defined as a Barthel index of <70. The association between low or high doses of rehabilitation and the primary outcome was assessed using multiple logistic regression analysis adjusted by baseline factors. The rate of ADL dependence at discharge was significantly lower in the high-dose rehabilitation group (low dose 81% vs. high dose 22%, P<0.001). Multivariate analysis showed a significantly lower ADL dependence at discharge among those who received high-dose rehabilitation (P<0.001). Increased RATs during the entire ICU admission period and during ICU admission after meeting the criteria for physiological stability was significantly associated with lower ADL dependence at discharge (P<0.001). Moreover, a higher RATs from low-level activity before meeting the criteria for physiological stability also showed a significant association with lower ADL dependence at discharge (P=0.047). ADL dependence was significantly lower among those who underwent high-dose rehabilitation. The RATs was consistently associated with ADL dependence at discharge.


Proofreading neutralizes potential error hotspots in genetic code translation by transfer RNAs.
The ribosome uses initial and proofreading selection of aminoacyl-tRNAs for accurate protein synthesis. Anomalously high initial misreading in vitro of near-cognate codons by tRNA(His) and tRNA(Glu) suggested potential error hotspots in protein synthesis, but in vivo data suggested their partial neutralization. To clarify the role of proofreading in this error reduction, we varied the Mg(2+) ion concentration to calibrate the total accuracy of our cell-free system to that in the living Escherichia coli cell. We found the total accuracy of tRNA selection in our system to vary by five orders of magnitude depending on tRNA identity, type of mismatch, and mismatched codon position. Proofreading and initial selection were positively correlated at high, but uncorrelated at low initial selection, suggesting hyperactivated proofreading as a means to neutralize potentially disastrous initial selection errors.


Human basophils express interleukin-4 receptors.
Interleukin-4 (IL-4), a multipotential lymphokine reputed to play an important role in the regulation of immune responses, interacts with a variety of hemopoietic target cells through specific cell surface membrane receptors. The present study was designed to investigate whether human basophils express IL-4 binding sites. For this purpose, basophils were enriched to homogeneity (93% and 98% purity, respectively) from the peripheral blood of two chronic granulocytic leukemia (CGL) donors using a cocktail of monoclonal antibodies (MoAbs) and complement. Purified basophils bound 125I-radiolabeled recombinant human (rh) IL-4 in a specific manner. Quantitative binding studies and Scatchard plot analysis revealed the presence of a single class of high affinity IL-4 binding sites (280 +/- 40 sites per cell in donor 1 and 640 +/- 45 sites per cell in donor 2) with an apparent dissociation constant, kd, of 7.12 x 10(-11) +/- 2.29 x 10(-11) and 9.55 +/- 3.5 x 10(-11) mol/L, respectively. KU812-F, a human basophil precursor cell line, was found to express a single class of 810 to 1,500 high affinity IL-4 binding sites with a kd of 2.63 to 5.54 x 10(-10) mol/L. No change in the numbers or binding constants of IL-4 receptors was found after exposure of KU812-F cells to rhIL-3 (a potent activator of basophils) for 60 minutes. No effect of rhIL-4 on 3H-thymidine uptake, release or synthesis of histamine, or expression of basophil differentiation antigens (Bsp-1, CD11b, CD25, CD40, CD54) on primary human CGL basophils or KU812-F cells was observed.


[Carcinosarcoma of the corpus uteri--a case report].
Sarcomas account for fewer than 5% of all cancers of the uterine corpus. We present the last classification of The International Society of Gynecology Pathologists for pure sarcomas and also for mixed epithelial-nonepithelial tumors of the uterine corpus. The paper concerns with the study of a case of carcinosarcoma, treated in the III-rd Clinic of Gynecology from Iaşi. This morphological diagnostic represents the most common epithelial-nonepithelial tumor affecting the uterus. Immunohistochemistry with EMA confirms the theory of the combined tumor with a unique origin.


The ADEP Biosynthetic Gene Cluster in Streptomyces hawaiiensis NRRL 15010 Reveals an Accessory clpP Gene as a Novel Antibiotic Resistance Factor.
The increasing threat posed by multiresistant bacterial pathogens necessitates the discovery of novel antibacterials with unprecedented modes of action. ADEP1, a natural compound produced by Streptomyces hawaiiensis NRRL 15010, is the prototype for a new class of acyldepsipeptide (ADEP) antibiotics. ADEP antibiotics deregulate the proteolytic core ClpP of the bacterial caseinolytic protease, thereby exhibiting potent antibacterial activity against Gram-positive bacteria, including multiresistant pathogens. ADEP1 and derivatives, here collectively called ADEP, have been previously investigated for their antibiotic potency against different species, structure-activity relationship, and mechanism of action; however, knowledge on the biosynthesis of the natural compound and producer self-resistance have remained elusive. In this study, we identified and analyzed the ADEP biosynthetic gene cluster in S. hawaiiensis NRRL 15010, which comprises two NRPSs, genes necessary for the biosynthesis of (4S,2R)-4-methylproline, and a type II polyketide synthase (PKS) for the assembly of highly reduced polyenes. While no resistance factor could be identified within the gene cluster itself, we discovered an additional clpP homologous gene (named clpPADEP) located further downstream of the biosynthetic genes, separated from the biosynthetic gene cluster by several transposable elements. Heterologous expression of ClpPADEP in three ADEP-sensitive Streptomyces species proved its role in conferring ADEP resistance, thereby revealing a novel type of antibiotic resistance determinant.IMPORTANCE Antibiotic acyldepsipeptides (ADEPs) represent a promising new class of potent antibiotics and, at the same time, are valuable tools to study the molecular functioning of their target, ClpP, the proteolytic core of the bacterial caseinolytic protease. Here, we present a straightforward purification procedure for ADEP1 that yields substantial amounts of the pure compound in a time- and cost-efficient manner, which is a prerequisite to conveniently study the antimicrobial effects of ADEP and the operating mode of bacterial ClpP machineries in diverse bacteria. Identification and characterization of the ADEP biosynthetic gene cluster in Streptomyces hawaiiensis NRRL 15010 enables future bioinformatics screenings for similar gene clusters and/or subclusters to find novel natural compounds with specific substructures. Most strikingly, we identified a cluster-associated clpP homolog (named clpPADEP) as an ADEP resistance gene. ClpPADEP constitutes a novel bacterial resistance factor that alone is necessary and sufficient to confer high-level ADEP resistance to Streptomyces across species.


Short-acting beta 2 agonists for stable chronic obstructive pulmonary disease.
Chronic Obstructive Pulmonary Disease (COPD) is a chronic condition characterised by progressive airflow limitation that is at most partially reversible. Despite the lack of reversibility patients often report symptomatic improvement with short-acting beta 2 bronchodilator medications. They are used on either an "as required" or a "regular plus as required basis" and they may be used in conjunction with other bronchodilator medicines such as ipratropium and methylxanthines. These medicines are used in the management of both stable and acute exacerbations of COPD. This review examined the effect of short-acting beta 2 bronchodilators given by inhalation in stable COPD. To determine the clinical effect and assess the adverse effects of inhaled short-acting beta 2 agonist bronchodilators compared with placebo in stable COPD. Only randomised controlled trials (RCTs) were considered. RCTs were identified using the Cochrane Airways Group database (CENTRAL). In addition, the reference lists of review articles and RCTs retrieved in full were searched for other potentially relevant citations. Only trials with adult patients with stable COPD, as defined by internationally accepted guidelines (ATS, ERS or BTS) were included in this review. All trials had a minimum duration of 7 days of regular treatment with short-acting beta 2 bronchodilators given by inhalation and compared with placebo. Data from trials where beta 2 agonists were used alone or in combination with other medicines (e.g. ipratropium bromide) were used only if there was a direct comparison between beta 2 bronchodilator alone and placebo. Outcomes were analysed as continuous or dichotomous outcomes, using standard statistical techniques. For continuous outcomes, the weighted mean difference (WMD) and 95% confidence intervals were calculated and for dichotomous outcomes, the odds ratio was calculated with 95% confidence intervals by Peto's methods. Funnel plots were used to test for publication bias. Thirteen studies were included in this review. Most had small sample sizes and some of the sutides used very short-acting outdated compounds. All the studies used a cross-over design and were of high quality. Spirometry done at the end of study period was measured after administration of treatment (post-bronchodilator) which showed both FEV1 (0.150 L/min, 95%CI: 0. 02-0.28) and FVC (0.310 L, 95%CI: 0.00-0.62) to improve significanly but slightly when compared to placebo. A few studies measured FRC, airway resistance or conductance at the end of the study period. In all cases these measurements were done several hours after treatment, and no significant differences (p>0.05 in all cases) were found between the bronchodilator and placebo groups. Walking test Large increases in 6MW distance was observed in two studies, however one study did not show any positive improvements. There was a large increase in the 12MW distance as shown by one study. Due to the small number of studies reporting this outcome no significant differences were found in the walking distance between the bronchodilator and placebo groups. Peak Flow Rate Both morning (36. 04 L/min; 95%CI: 0.80-71.27) and evening (36.68 L/min; 95%CI: 2. 47-70.89) PEFR were significantly higher during active treatment than during placebo. Symptoms Breatlessness was measured on various scales therefore data that were presented in a suitable form were combined using standardized means for inclusion in the analysis. A significant improvement (-0.33; 95%CI: -0.58 to -0.07 with p=0.01) in the breathlessness score was observed during treatment with beta-2 agonist when compared to placebo. Cough was reported to improve significantly (data not usable) during treatment with beta2 agonist in one study but not in two others. A non-significant decrease in sputum production was reported by Wilson 1980, however four other studies reported no


Disruptive mRNA folding increases translational efficiency of catechol-O-methyltransferase variant.
Catechol-O-methyltransferase (COMT) is a major enzyme controlling catecholamine levels that plays a central role in cognition, affective mood and pain perception. There are three common COMT haplotypes in the human population reported to have functional effects, divergent in two synonymous and one nonsynonymous position. We demonstrate that one of the haplotypes, carrying the non-synonymous variation known to code for a less stable protein, exhibits increased protein expression in vitro. This increased protein expression, which would compensate for lower protein stability, is solely produced by a synonymous variation (C(166)T) situated within the haplotype and located in the 5' region of the RNA transcript. Based on mRNA secondary structure predictions, we suggest that structural destabilization near the start codon caused by the T allele could be related to the observed increase in COMT expression. Our folding simulations of the tertiary mRNA structures demonstrate that destabilization by the T allele lowers the folding transition barrier, thus decreasing the probability of occupying its native state. These data suggest a novel structural mechanism whereby functional synonymous variations near the translation initiation codon affect the translation efficiency via entropy-driven changes in mRNA dynamics and present another example of stable compensatory genetic variations in the human population.


Dietary levels of plant phenols and other non-nutritive components: could they prevent cancer?
Several non-nutritive components in fruits, vegetables, herbs and spices have been found to inhibit tumour formation in experimental animals exposed to carcinogens. The active non-nutritive components vary with respect to their chemical structures, and may be classed as phenols, terpenes, indoles, isothiocyanates, allyl sulphides or others. They also seem to work by different mechanisms, being inducers or inhibitors of various enzymes, antioxidants, scavengers of reactive metabolites, or inducers of apoptosis. The dietary levels are generally in the order of 1-100 mg/day for most classes of compounds in the Danish population, and similar levels are expected in most northern European countries. These levels are very low compared with the levels used in most animal experiments, where non-nutritive factors have individually been shown to have inhibitory actions on tumorigenesis. Human long-term intervention trials with antioxidants have generally been discouraging. In human short-term intervention studies, where increased dietary levels of specific vegetables or fruits are studied, doses are also comparatively low. Effects on important enzymes have been reported in several such studies, indicating that low levels of non-nutritive factors could influence carcinogenesis by specific mechanisms. Meta-analyses of cohort studies on specific food items rich in specific non-nutritive components, indicate that carotenoid- or glucosinolate-rich foods protect against some cancers, while flavonoid rich food items do not uniformly show protective effects.


A mechanosensory receptor required for food texture detection in Drosophila.
Textural properties provide information on the ingestibility, digestibility and state of ripeness or decay of sources of nutrition. Compared with our understanding of the chemosensory assessment of food, little is known about the mechanisms of texture detection. Here we show that Drosophila melanogaster can discriminate food texture, avoiding substrates that are either too hard or too soft. Manipulations of food substrate properties and flies' chemosensory inputs indicate that texture preferences are revealed only in the presence of an appetitive stimulus, but are not because of changes in nutrient accessibility, suggesting that animals discriminate the substrates' mechanical characteristics. We show that texture preference requires NOMPC, a TRP-family mechanosensory channel. NOMPC localizes to the sensory dendrites of neurons housed within gustatory sensilla, and is essential for their mechanosensory-evoked responses. Our results identify a sensory pathway for texture detection and reveal the behavioural integration of chemical and physical qualities of food.


Environmental conditions and community evenness determine the outcome of biological invasion.
Biological invasion is widely studied, however, conclusions on the outcome of this process mainly originate from observations in systems that leave a large number of experimental variables uncontrolled. Here using a fully controlled system consisting of assembled bacterial communities, we evaluate the degree of invasion and the effect on the community functionality in relation to the initial community evenness under specific environmental stressors. We show that evenness influences the level of invasion and that the introduced species can promote functionality under stress. The evenness-invasibility relationship is negative in the absence and neutral in the presence of stress. Under these conditions, the introduced species is able to maintain the functionality of uneven communities. These results indicate that communities, initially having the same genetic background, in the presence of the same invader, react in a different way with respect to invasibility and functionality depending on specific environmental conditions and community evenness.


Care of the ocular prosthesis.
The goal of the ocular prosthetic procedure is to return the patient to a normal appearance and lifestyle. Modern eye prostheses can give the patient an excellent physical and cosmetic result. In the final analysis, the success or failure of the long-term use of the prosthesis is dependent on the cooperation of the patient in the care of his ocular prosthesis. It is important for the patient to be aware of and proficient in the care of his prosthesis. Patient education and professional follow-up will ensure the best prosthetic fit, appearance, and health of the anophthalmic socket.


Regulated in development and DNA damage responses 1 (REDD1) links stress with IL-1β-mediated familial Mediterranean fever attack through autophagy-driven neutrophil extracellular traps.
Familial Mediterranean fever (FMF) is an IL-1β-dependent autoinflammatory disease caused by mutations of Mediterranean fever (MEFV) encoding pyrin and characterized by inflammatory attacks induced by physical or psychological stress. We investigated the underlying mechanism that links stress-induced inflammatory attacks with neutrophil activation and release of IL-1β-bearing neutrophil extracellular traps (NETs) in patients with FMF. RNA sequencing was performed in peripheral neutrophils from 3 patients with FMF isolated both during attacks and remission, 8 patients in remission, and 8 healthy subjects. NET formation and proteins were analyzed by using confocal immunofluorescence microscopy, immunoblotting, myeloperoxidase-DNA complex ELISA, and flow cytometry. Samples from patients with Still's disease and bacterial infections were used also. The stress-related protein regulated in development and DNA damage responses 1 (REDD1) is significantly overexpressed during FMF attacks. Neutrophils from patients with FMF during remission are resistant to autophagy-mediated NET release, which can be overcome through REDD1 induction. Stress-related mediators (eg, epinephrine) decrease this threshold, leading to autophagy-driven NET release, whereas the synchronous inflammatory environment of FMF attack leads to intracellular production of IL-1β and its release through NETs. REDD1 in autolysosomes colocalizes with pyrin and nucleotide-binding domain, leucine-rich repeat/pyrin domain-containing 3. Mutated pyrin prohibits this colocalization, leading to higher IL-1β levels on NETs. This study provides a link between stress and initiation of inflammatory attacks in patients with FMF. REDD1 emerges as a regulator of neutrophil function upstream to pyrin, is involved in NET release and regulation of IL-1β, and might constitute an important piece in the IL-1β-mediated inflammation puzzle.


Early development of vocal interaction rules in a duetting songbird.
Exchange of vocal signals is an important aspect of animal communication. Although birdsong is the premier model for understanding vocal development, the development of vocal interaction rules in birds and possible parallels to humans have been little studied. Many tropical songbirds engage in complex vocal interactions in the form of duets between mated pairs. In some species, duets show precise temporal coordination and follow rules (duet codes) governing which song type one bird uses to reply to each of the song types of its mate. We determined whether these duetting rules are acquired during early development in canebrake wrens. Results show that juveniles acquire a duet code by singing with a mated pair of adults and that juveniles gradually increase their fidelity to the code over time. Additionally, we found that juveniles exhibit poorer temporal coordination than adults and improve their coordination as time progresses. Human turn-taking, an analogous rule to temporal coordination, is learned during early development. We report that the ontogeny of vocal interaction rules in songbirds is analogous to that of human conversation rules.


[Surgical aspects of the new TNM system for lung cancer].
Recent results of basic research in lung cancer and development of new antitumoral drugs provided the bases for the revision of TNM system of lung cancer. In addition, the VI-th Edition of TNM classification was based on a relatively small database anyway. Multicentric analysis and biostatistical evaluation were carried out by the initiation of IASCL. 100869 patients were collected and 81015 cases were included in the analysis finally (NSCLC: 67725, SCLC: 13290). The aim of the study was to modify T, N as well as M factors of the classification. The recommendations were based on a large international database and survival analysis of that. It is expected that this change will influence treatment algorithms of lung cancer and it will improve survival of patients therefore.


Endovascular recanalization of the aorto-iliac segment: imaging and approaches.
Endovascular catheter techniques are most useful and successful in the aorto-iliac arteries. As in other territories, wire recanalization, balloon angioplasty, and endoluminal stent placement are most applicable. For the surgeon, imaging considerations are most important since the operating room must be equipped with the proper capabilities for endovascular surgery. Techniques of catheterization and angiographic visualization of the arteries must be learned and understood clearly before these procedures are undertaken. A variety of occlusive lesions involving the aorta and iliac arteries can be treated adequately by means of nonsurgical catheter-based methods which add a significant new dimension to the vascular surgeon.